The compound of (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(methane-sulfonyl-methyl-amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-hept-6-enoic acid (rosuvastatin) is known from the prior art. It was described for the first time in European Patent No. 521471 in acid form and in the forms of some pharmaceutically acceptable salts including calcium salt of the formula (II) and ammonium salt. The zinc salt of rosuvastatin (2:1) of the formula (III) was described first in the Hungarian patent application P0600293 and in international patent application No. WO2007/119085.
According to the process described in the European patent No. 521471 rosuvastatin salts are prepared by saponification of rosuvastatin alkyl esters of the general formula (V),
the thus obtained rosuvastatin salt is optionally converted to free acid and the obtained salt or acid is converted to a pharmaceutically acceptable salt, preferably to calcium salt.
Several processes are known from the prior art wherein rosuvastatin calcium salt of the formula (II) is prepared via different intermediates. The process via a rosuvastatin ketal intermediate compound of the general formula (VI)
is described in International Patent Applications WO 2006/126035 and WO 2005/042522, while the ketal acid salts according to the formula (VII)
and the rosuvastatin ketal acid of the formula (VIII)
are disclosed as intermediates in International Patent Application WO 2006/126035. Processes using the compound of the formula (V) as starting compound are described e.g. in International Patent Applications WO 2003/097614 and WO 2005/023778. A process for the preparation of calcium salt from rosuvastatin lactone of the formula (IX)
is described in International Patent Applications WO 2005/040134, WO 2005/077916 and WO 2006/136407.
According to the prior art there are processes in which rosuvastatin calcium salt of the formula (II) is prepared from any of the rosuvastatin salts formed with amines. A common feature of these processes known from the prior art is that rosuvastatin calcium salt of the formula (II) is separated from aqueous media.
As known from prior art, the conversion is carried out by the following method: a salt of rosuvastatin formed with an amine is converted to a sodium salt, then in an aqueous solution a calcium salt is obtained from the sodium salt and the calcium salt is isolated.
In most of the cases described in prior art, preparation starting from salts formed with amines is carried out via the sodium salt of rosuvastatin. International Patent Application WO 01/060804 describes crystalline forms of ammonium, methyl-ammonium, ethyl-ammonium, diethanol-ammonium, tris-(hydroxymethyl)-methyl ammonium, benzylammonium and 4-methoxybenzylammonium salts of rosuvastatin. Furthermore, the conversion of these crystalline salts into rosuvastatin calcium salt is also disclosed in such a manner that the ammonium salts are converted to rosuvastatin sodium salt with sodium hydroxide in an aqueous medium, then the product is converted to calcium salt of the formula (II) and the product is filtered off from the aqueous solution. The purity of the product is not mentioned in the description.
International Patent Application No. WO 2005/051921 discloses the purification of rosuvastatin calcium salt via crystalline forms of isopropyl- or cyclohexyl-ammonium salts in several steps. Rosuvastatin calcium salt is converted to rosuvastatin of the formula (I), then it is transformed into its isopropyl- or cyclohexyl-ammonium salt using ethyl acetate as solvent. The rosuvastatin calcium salt is obtained through rosuvastatin sodium salt from rosuvastatin ammonium salts mentioned above after filtration from an aqueous solution with a 73.6% yield. However, the purity of the product has not been disclosed.
International Patent Application No. WO 2005/077916 discloses crystalline forms and amorphous forms of rosuvastatin cyclohexyl-, dicyclohexyl-, isopropyl-, diisopropyl- and (S)-1-methylbenzyl-ammonium salts. The listed salts are transformed into rosuvastatin calcium salt of the formula (II) in such a manner that rosuvastatin ammonium salt is converted to rosuvastatin lactone of the formula (IX), which is converted to sodium salt and reacted with a calcium source in an aqueous medium, then the amorphous rosuvastatin calcium salt is filtered off. Furthermore, the description discloses a recrystallisation process for the purification of rosuvastatin ammonium salts and the rosuvastatin calcium salt obtained from them with a purity higher than 99.5%. The amount of the diastereomer impurity is high, according to said patent application the amount of the impurity can be reduced to about 0.25% if the process disclosed is used. However, the active ingredient having the above-mentioned purity does not meet the limits of the internationally accepted ICH requirements because the highest acceptable amount of the impurity is 0.15%.
International Patent Application No. WO 2008/067440 discloses the dehydroabietine salt of rosuvastatin from which rosuvastatin calcium salt is prepared through sodium salt in water. The product is filtered off from an aqueous solution. The HPLC purity of the rosuvastatin calcium salt according to the example is 99.80%, the amount of diastereomer impurity is 0.14%, which is near to the accepted limit of 0.15%.
The above-mentioned patent applications do not disclose the tert-butylammonium salt of rosuvastatin of the formula (IV). International Patent Applications WO 2007/125547 and WO 2008/044243 disclose a new process for the preparation of rosuvastatin tert-butylammonium salt and for the preparation of rosuvastatin calcium salt in an aqueous solution via rosuvastatin sodium salt and isolating by filtration. The purity of the product is not mentioned.
The conversion of different rosuvastatin ammonium salts to calcium salt directly instead of converting via sodium salt is disclosed in International Patent Applications WO 2004/014872 and WO 2006/136407. The reaction is carried out in water according to the inventors of both inventions.
International Patent Application WO 2004/014872 protects a process using special process parameters which result in an increased efficiency of the filtration of the precipitated salt. In course of the process, the rosuvastatin calcium salt is obtained from certain water soluble salts of ammonium compounds with rosuvastatin (ammonium, tris-(hydroxymethyl)-methylammonium, methylammonium) by addition of calcium chloride to them and the filtration off from the aqueous solution. The purity of the product is not mentioned in the description.
International Patent Application WO 2006/136407 discloses a process for the preparation of rosuvastatin calcium salt free from contaminants. In course of the process, a rosuvastatin ester is hydrolyzed in a mixture of water and an aprotic solvent and the obtained ammonium salt (e.g. isopropylammonium, N-methylcyclohexylammonium etc.) is boiled in water with a calcium source and rosuvastatin calcium salt is obtained free from alkali metals, in the purity of 99.9% (HPLC). The HPLC purity given by the authors refers to the product before drying. The tert.-butylammonium salt of rosuvastatin is not mentioned among the used starting compounds according to the application.
Rosuvastatin zinc salt is the subject of our Hungarian patent application No. P0600293 and our International Patent Application WO 2007/119085. In our Hungarian patent application No. P0700667 processes were disclosed for the preparation of rosuvastatin zinc salt of the formula (III), wherein rosuvastatin of the formula (I) or a sodium salt thereof, alkylester of rosuvastatin of the formula (V), rosuvastatin lactone of the formula (IX) or rosuvastatin ketal ester of the formula (VI) were used as starting compound.
International Patent Application WO2008/015563 discloses a process for the preparation of rosuvastatin zinc salt of the formula (III) from tert-butylammonium salt of rosuvastatin via sodium salt by filtration of the product from an aqueous solution. The purity of the zinc salt is 99.41%.
There is no other process mentioned in the prior art for the preparation of rosuvastatin zinc salt of the formula (III) from rosuvastatin ammonium salts.